Many adverse side reactions of antitumor drugs resemble responses to bacterial endotoxin. We have demonstrated that many antitumor agents given in combination with a sublethal dose of bacterial lipopolysaccharide can cause an increased rate and extent of death in challenged BALB/c mice. The time of administration of drug with respect to bacterial endotoxin is determinative. This project will evaluate the hypothesis that some of the adverse reactions seen in cancer patients undergoing chemotherapy may reflect this type of toxic synergy. Our first goal will be to determine the physiological bases of selected toxic synergies. Daunorubicin in combination with Salmonella typhosa endotoxin in the BALB mouse will be used as a model system for measuring effects on clearance and detoxification of the administered agents. Our second goal is to assess the role of the normal flora in precipitating adverse reactions to antitumor drugs. Our third goal will be to discover means for preventing these harmful interactions. Our fourth goal is to determine whether selected new antitumor candidate drugs given in combination with bacterial endotoxin will result in enhanced lethality of the treated mice.